Chronic epithelial injury is a hallmark of inflammatory lung disease. Mucosal repair is mediated by a cell state transition of normal epithelial cells, known as Type II epithelial-mesenchymal transition (EMT), responsible for myofibroblast expansion, epithelial trans-differentiation, and subepithelial fibrosis. Currently, very little is known about the factors initiating type II EMT.
Chronic lung disease is the second largest cause of mortality worldwide (Durham et al., Biochim Biophys Acta, 2011, 1810(11):1103-09). A pathological hallmark of asthma is disruption of the epithelial cell barrier (Lambrecht and Hammad, Nat Med, 2012, 18(5):684-92). Upon exposure to respiratory viruses or environmental oxidants, resident epithelial cells undergo epigenetic and phenotypic changes to produce pro-inflammatory mediators, express extracellular matrix, and expand the myofibroblast population (Ijaz et al., World Allergy Organ J, 2014, 7(1):13). These phenotypic changes are associated with enhanced motility, resistance to reactive oxygen species (ROS) and expression of fibrotic genes, processes together known as Type II EMT (Kalluri and Weinberg, J Clin Invest, 2009, 119(6):1420-28). Although important in tissue repair, unregulated EMT plays a critical cellular role in the progression of chronic human pulmonary fibrotic diseases, diseases including atopic asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF) (de Boer et al., Can J Physiol Pharmacol, 2008, 86(3):105-12). EMT has also recently been observed in chronic airway disease associated with cystic fibrosis or severe respiratory syncytial virus (RSV), a risk factor for the development of allergic asthma later in life (Kaltenborn et al., Hum Mol Genet, 2012, 21(12):2793-806). All of this evidence suggests that EMT plays important roles in the pathogenesis of airway remodeling in response to environmental stressors.
There remains a need for additional methods and compositions for treating EMT related to fibrosis, asthma, or COPD.